| Summary: | 博士 === 高雄醫學大學 === 牙醫學研究所 === 99 === Areca nut/betel quid (BQ, Areca catechu) is said to be the fourth most commonly used psychoactive substance in the world. Many people acquire the habit of chewing BQ due to its physiological effects, including increased stamina and a general feeling of well being. It shows mild psycho-stimulatory effects but with prolonged use, there is an increased risk of oral precancerous lesion (OPL) and oral cancer, and is an increased risk of extra-oral diseases such as diabetes, hypertension, central obesity, and so on. In addition, previous studies suggested that genetic factor is involved in susceptibility to the development of the diseases. It has been showed that angiotensin- converting enzyme (ACE) and cytochrome P450s (CYPs) polymorphhisms are associated with cancer susceptibility. ACE is differentially expressed in several malignancies and influences tumor cell proliferation, tumor cell migration, angiogenesis, and metastatic behavior. In addition, CYPs are the phase I enzymes in the activation pathway. To further clarify the role of ACE and CYP1A1 polymorphisms in association with risk of OPL and oral cancer and extra-oral diseases in betel quid chewers. The present study enrolled aboriginal and Hen subjects of Southern Taiwan with a high prevalence of BQ chewing to investigate: (A) ACE and CYP1A1 polymorphisms in association with risk of OPL and oral cancer in BQ chewers; (B) inflammatory cytokines and ACE polymorphisms and BQ chewing in association with extra-oral diseases. A total of 61 BQ chewers having OPL were studied to compare with 61 asymptomatic BQ chewers matched for BQ chewing duration and dosage. The frequency of homozygote for ACE DD genotype and D variant is significantly higher in the case subjects than those of the controls. Further, the DD genotype (AOR = 8.10, 95% CI = 2.04-32.19, P = 0.003) and D allele (AOR = 5.26, 95% CI = 2.13-13.00, P = 0.0003) are significantly associated with higher risk of OPL by conditional logistic regression analysis. Further, ACE I/D polymorphisms were studied in 88 OPL patients, 186 oral cancer patients, and 120 without any oral lesions control subjects, all study subjects were male gender and BQ chewers. The results found that ACE DD genotype is associated not only with higher risk of OPL and oral cancer but also is associated with lymph node metastasis in Hen population of BQ chewers. Using immunohistochemical method, we showed up-regulation of ACE in basal keratinocytes in dysplasias as well as in the central cells of squamous cell carcinomas. However, in the present another study, the association of cytochrome P4501A1 (A2455G) polymorphism with risk of OPL in BQ chewers, CYP 1A1 ploymorphism was not found in association with OPL in Taiwan Southern aboriginal population with BQ chewing. The results may be dut to racial differences.
To study the extra-oral effects of BQ chewing a total of 1,258 aboriginal subjects of Southern Taiwan were enrolled. BQ chewing subjects had significantly higher prevalence of dysglycemia, central obesity, hyper-triglyceridemia, and metabolic syndrome (MetS) than those of non-chewers, and was independently associated with MetS. A total of 189 BQ chewing subjects and 256 non-chewing controls were studied. BQ chewers with the DD genotype had significantly lower blood pressure, pulse pressure and prevalence of hypertension compared to those of chewers with II or ID genotypes. Multiple regression analysis confirmed that BQ chewers with the DD genotype accounted for a significant age, sex, and waist to hip ratio adjusted decrease in systolic blood pressure. This finding supports the hypothesis that BQ chewing and ACE I/D polymorphism may regulate the human metabolic effect.
In conclusion, the ACE gene polymorphism may be considered as a factor of increased susceptibility to OPL and oral cancer and associated with the induction of lymph node metastasis of oral cancer disease in Taiwanese. In addition, chronic BQ chewing is an independent contributor of MetS. Inflammatory cytokines are involved in BQ chewing related metabolic derangements. Further, concomitant genetic susceptibility and environmental factors determine the level of blood pressure. This study suggested that BQ chewing related systemic effects are not to be ignored and evidenced that genetic polymorphism and inflammatory cytokines play an important role in the BQ induced oral and extra-oral disease pathophylogy.
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